CA1105026A - 4a-aryl-octahydro-1h-2-pyrindines - Google Patents

Abstract

Abstract of the Disclosure Trans-4a-phenyl and substituted phenyl 2,3,4,?,5,6,7,7a-octahydro-1H-2-pyrindines having a 2-substituent are disclosed. Such compounds are useful as analgesic agents having mixed agonist and antagonist properties. The compounds can be prepared by reacting a 4a-aryl-2-substituted-3,4,4a, 5,6,7-hexahydro-2-pyrindine with hydrogen and platinum oxide.

Description

.

In recent years, mUch e~fort has been devoted to the synthesis of drugs, i.eO analgesics, capable of relieving the sen~ation of pain. Several of the currently available analgesics are limited ln their use due to various undesirable side ef~ects which ~requently accompany their continued use. Such side efects include addiction and allergy. Illus-trative of new analgesic drugs which have recently been discover~d are the decahydroisoquinolines, partic--ularly tha 4a-aryl-tran~-decahydroisoquinolines which are described in Belgian Patent No. 802~557O
The presen~ invention relates to a group of trans 4a-aryl-2-sub~tituted-octahydro-lH 2-pyrindines.
Such compounds are somewhat structurally related to the aforemen-tioned isoquinoline derivatives; however, the compounds of ormula (I) below have not heretofore been synthe~ically available. Simple unsubstituted pyrindi.ne analogs are known in the li~erature.
Volodina e~ al.~ or example, prepared certain octa- -hydro-2-pyrinclines, none o~ which were substituted at the 4a~position; Dokl, Akad. Nauk USSR 173(2), 342~5 (1967) cf. C.A~ Vol. 67, 6~34(1967). Similarly, Prochazka et al. prepared a trans-octahydxo-2-, ., . .:

pyrindine lacking a 4a-substituent, Coll. Czech. Chem.
Commun., 31(9), 3824-8(1966), Cf. C.A. Vol. 65, 13651 (1966). Recently, Zimmerman prepared the cis-4a-aryl-2-substituted-octahydro-lH-2-pyrindines which are s analgesics and are disclosed in Belgian Patent NoO
8~0,314.
This invention provides trans-4a-phenyl and substituted phenyl 2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindines not heretofore known or available, and intermediates useful in their preparation.
This invention relates to new bicylic compounds characterized as being octahydro-lH-2-pyrindines, alternatively referred to as hexahydro-l~-cyclopenta[c]pyridines. Specifically, the invention provides trans-4a-aryl-2-substituted~2,3,4,4a,5,6,7,7a-. _ .
oc~ahydro-lH-2-pyrindines of the general formula /~ ' ii T--Rz /5\ /4\
/ ~a 3T

~ ~/ ~ ~ -R~
1 is hydrogen, Cl-C8 alkyl, ~H R

-(CH2) (X)m ~ ~ , C~Cl--C7 alkyl, CR3, or n ~ R

~--9~4 C-(CH2)n_l ~(X)m \~_ ~ ; in which R3 , ~ . ., , is C2-C7 alkenyl, C3-C6 cycloalkyl, furyl, or tetra-hydrofuryl; R4 and R5 independently are hydrogen, Cl-C3 alkyl, or halogen; n is 0, 1, 2, or ~, m is 0 or 1, excep~ that when m is 0, n is other than 0; X is 5 CO~ C~OH, CH=CH, S, or O, except that when ~ is O, X
is other than S or O; R2 is hydrogen, hydroxy, Cl-C3 alkoxy, or Cl-C3 alkanoyloxy; and the non-toxi~ pharma-ceutic:ally acceptable acid addition salts thereo~.
Addi~ionally enc:ompossed within the scope of 10 formula ~I ~ are. intermediat . compoundR havins the O O
above formula wherein ;R1 is C-C:l-C7 alkyl, CR3 in which R3 has the above defined meaning,.
~0=->~R4 ~5 have the above defined meaning. .
~ preferred group of compounds o~ formula (I ) wherein Rl is Cl--C8 alkyl or CH2R3 in which R3 is C2-C7 alkeny7 or C3-C6 c:ycloalkyl. A m20 group o~ compounds wi1:hin thi~ la~ter preferred group are those of formula (I) wher~3in R;2 i~ hydroxy methoxy.
. An espec:ially pre~erred group o intermediate c:ompounds are ~hose of formula (I) wherein Rl is hydrogen.
The present ~nvent~on also pn~dbs a pnx~ss ~or prq~in~ the ~5 trans-o~vu~ of the ~ral ~o~n~a r R-F~2 / ~¦/ 't ~II) \ / \ /~ ~<; , ~ ,.

- - .
,~ ` :
.

:: ' wherein:
Rl is hydrogen, Cl-C8 alkyl, CH2R3, or ~~CH2)n~(X)m~~ ~ in which R3 is C2-C7 alkenyl, C3-C6 cycloalkyl~
furyl, or tet~ahydrofuryl;
R~ and R5 independently are hydrogen, Cl-C3 alkyl, or halogen;
n i5 O, 1, 2, or 3;
m is 0 or 1, except that when m is 0, n is other than 0;
X .is~COI CHOH, CH-CHt S, or 0, except that when n i5 0, X iS other than S or 0;
R2 is hydrogen, hydroxy, Cl-C3 alkoxy, or Cl-C3 alkanoyloxy; and the pharmaceutically acceptable acid addition salts thereof;
~ which comprises reacting a compou~d of the :: 20 general formula ~ -R~

ZS
-R

wherein:
R~ is hydrogen, Cl-C8 alkyl, CH2R3, ~ ( 2)n (X)m ~ ~ , C-Cl-C7 alkyI/ CR3 , or :~ :
.~ ~

~, ~ , . - .

X--4466K _5_ C-(CH2)n-l ~X)m \ _ in which:
R3 is C3-C6 cycloallsyl, furyl, or tetra hydrofuryl;
R4 and R5 independently are hydrogen, Cl-C3 alkyl, or halogen;
n is 0, 1, 2, or 3;
m is Q or 1, except that whe~ m i5 0, n i~ other than 0;
is CO, CHOH, CH~C~, S, or 0, except that when n is 0, X is other than S or 0;
R2 is hydrogen, hydroxy, Cl-C3 alkoxy, or ~1-C3 al~canoyloxy;
:~ with hydro~en and platin~m oxide, followed - by alkylation when ~1 is hydrogen to obtain a compound . o~ formula (II) in which Rl is defined as before, optionally de-etherifying when R2 is Cl-C3 alkoxy to obtain a compound of ~ormula (II) in which R2 is hydroxy, and optionally acylating a compound of ormula (I~) in which R2 is hydroxy to obtain a compound o~ formula (II) in which R2 is Cl-C3 alkanoyloxy, and, when desired, forming the pharma-~ 25 ceutically acceptable acid addition salt thereof by conventional means.
As u~ed throughout the pres~nt spec~ication ; and in the appended claims, the term "Cl-C8 alkyl"
xefers to bo~h straight and }: ranched chains o~ eight 30 carbon atoms ox l~s. Examples of typical Cl-C8 alkyl ~roups include me~hyl, ethyl, propyl, butyl, isopropyl, i~obutyl, pentyl, 3-methylpentyl, 1, 2-.

`:

.

- . . . .. ..
.

..
. ~ , dimethylpentyl, 2-methylbutyl, 3-ethylpentyl, n-octyl, 2-methylheptyl, isoheptyl, 3-ethylhexyl, 1,3,3-trimethylpentyl ! and related groups.
The term "CH2R3, in which R3 is C2-C7 allcenyl" refers to both straight and branched alkenyl groups having eight or less carbon atoms, including groups such as allyl, 3-butenyl, 2-pentenyl~ 3-pentenyl, 2~methyl-2-buten~l, 3-methyl-3 pentenyl, 3-isohexenyl, 2-~thyl 3-butenyl, 4-hexenyl, 3-methyl-2~pente~yl~ 3-octenyl, 2-isooctenyl, 2-i~opropyl-3-butenyl, 2,3-dimethyl-2 but~nyl, 5-heptenyl, 6-octenyl, 2-methyl-3-heptenyl, and related alkenyl groups.
Additionally included within the deinition of Rl in formula (I) is the group represented by CH2R3 in which R3 is C3-C6 cycloalkyl. Such groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl. Rl can also represent groups such as 2-tetrahydrofurylmethyl, 3-tetrahydrofuryl-methyl, and 3-furylmethyl.
In formula (I~, Rl can also he a group of >~ 4 ~he formula -(CH2)n-(X)m ~~ ~ in which n is 0, 1, 2, or 3, m is 0 or 1, except that when m is 0, n is other than 0; X is CO, C~O~, CH--CH, S or O, except that when n i~ O, X is other than S or O; and R~ and R5 inde-pendently ar~ hydrogen, Cl-C3 alkyl, or halogen. In such ~ormula, the term 'ICl-C3 alkyl" includes methyl, ethyl and propyl. "Halogen" re~ers to fluorine, . .

', .
- ,, -, . ~ . .

:: . .: - ~ . . : : : . :

~if~ 6 chlorine, bromine and iodine. Examples of typical R
group~ represented by this partial formula include benzyl, 2-phenylethyl, 3-phenylpropyl, 3-methylbenzyl, 4-chlorobenzyl, 2,4-dibromobenzyl, 2-(2-methyl-5-ethylphenyl)ethyl, 3-(4-i~opropylphenyl)propyl, benzoylmethyl, benzoylethyl, 4-iodobenzoylmethyl,

2-methyl-4-chlorobenzoylmethyl, 2-phenyl-2-hydroxy-ethyl, 3-phenyl~3-hydroxypropyl, 2-(4-fluorophenyl)-2-hydroxyethyl r phenoxymethyl, 3,$ diethylphenoxy~
methyl~ 3-phenylthiopropyl, 2~methylphenylthiomethyl,

3,5-dichlorophenyl~hiomethyl, 3-chloro-5-bromophenyl thiomethyl, and related groups.
When Rl in formula (I) is hydrogen, the unsubs~ituted 2-position can be further reacted by acylation and reduction (either when the ~1~7a_ bond is reduced or separately with Zn/acetic acid or catalytic hydrogenation), or alkylation (particularly to obtain the group where Rl is CH2R3 in which R3 is C2-C7 alkenyl).
Compounds of formula (I) ~as indicated by formula (II)] which are thus readily provided by reducing the ~1~7a-bond o a 4a-aryl-2-substituted-3,4,4a,5,6,7-hexahydro-2-pyrindine o formula (III) a~cording to the above-described procedures include, among other~:
4a-phenyl-2,3,4,4a,5!6,7,7a-octahydro-lH-2-pyrindine;

4~-(3-methoxypheny~ 3~4~4a~s/6~7~7a octahydro-lH-2-pyrindine;
4a-(3-ethoxyphenyl)-2-methyl-2,3,4,4a,5, 6,7,7a-octahydro-lH-2-pyrindine;
4a-phenyl-2-e~hyl-2,3,4,4a,5,6,7,7a-~ octahydxo-lH-2-pyrindine;

:~

, . : .
: .:

.

4a-(3-isopropoxyphenyl)-2-benzyl-2,~,4 4a,5 r 6 / 7,7a-octahydro-lH-2-pyxindin2;
4a-phenyl-2-isQbutyl-2,3,4,4a,5,6,7,7a~
octahydro-lH-2-pyrindine;
54a-(3-me hoxyphenyl ? -2- ( ~-ethylhexyl)-2,3 t 4,4a,5,6,7,7a-octahydro-lH-2-pyrindine; and 4a-(3~ethoxyphenyl)-2-~3-chlorobenzyl)~
2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine.
As was hereinbefore noted, very important intermediates or preparing all of the pyrindine derivatives of formula (I) are the 2-unsubstituted pyrindine derivatives, those in which Rl in formula (II) is hydrogen. Such compounds can be readily alkylated or acylated at the 2~position to provide pha~nacologically active o~tahydropyrindines o~
formula (I), or in the case of the N-acylated deriv-atives, to provide intermediates which are ~asily converted to the active analgesics of formula (I).
--It is ~herefore often desirable to prepare, according to the above-described processes, 4a-aryl-2-~ubsti-tuted-2~3,4~4a,5,6,7,7a-octahydro-lH-2-pyrindines in which the 2~substituent i5 readily removable so as to provide the corxe~ponding 2-uns~stituted octahydro-pyrindine dexivatives. The N-methyl and N-benzyl groups are readily cleavable to aEford the corre-sponding 2-unsubstituted pyrindine derivative. The 2-methyl pyrindine derivatives can be reacted with a haloforma~e ester such as phenyl chloroformate or ethyl chloroormate to afford the corresponding carbamate at ~he pyeindine 2-posi~ion. Such carbamate :

:

,. ., ... ~....... .
: . .
- ... . . ....... ...... . .

- , : ~ .. ~ . : . ... .. . . : ~

- ~ \
rs~/~

X-4466K _g_ is then reacted with an aqueous base such as sodium hydroxide to effect cleavage of the 2-carbamate moiety and thus provide the correspondiny 2-unsub-stituted pyrindine deri~ative. Such method for the cleavage of an N-methyl group is that of Abel-Monen and Portoghese as described in J. Med. Chem., 15, 208(1972).
Similarly, the aforementioned 4a-aryl~2-benzyl-2~3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindines are readily converted to the corresponding 2-unsubstituted pyrindine derivative by simple debenzylation. Such debenzylation may be achieved by catalytic hydrogention, utilizing ~or instance a catalyst such as five percent palladium suspended on carbon. Such debenzylation reactions axe quite yeneral for preparing secondary amines and are described in detail by Hartung and Simonof, Ory. Reactions, 7, 277(1953) t and by Loenard and Fuji, J. Amer. Chem. Soc., 85, 3719 (1963).
As can readily be seen from the foreyoing discussion, the followiny representative 2-unsub-stituted pyrindine derivatives, formula (II) where Rl is hydrogen, are also importan~ intermediates for the preparation of the pyrin~ines o~ ~ormula (I).
4a-phenyl~2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine;
4a-(3-methoxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro lH-2-pyrindine;
4a-(3-ethoxyphenyl)-2,3,4,4a,5,6~7,7a-octahydro-lH-2-pyrindine; and 4a-(3-isopropoxyphenyl)-2,3,4,4a,5,6,7,7a-ootahydro-lH-2-pyrlndine.

' ' .
~: :

- . . . .

, . . . .. ,: . , . :

2~

The 4a-aryl-2-unsubstituted-2,3,4,4a,5, 6,7~7a-octahydro-lH-2-pyrindines thus prepared can be alkyla~ed by normal procedures to provide pharma-cologically active 2-substi~uted pyrindine derivatives, or can be acylated to provide intermediates which are readily converted to active analgesic drugs. For example, a 4a-aryl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine can be alkylated at the 2-position by xeaction with essentially any reactive derivative of an alkyl group~ Such alkylating agents are compounds of the formula Rl-Z in which Rl is as defined here-inabove and Z is any of a number of groups commonly referred to as good lea~ing groups. Groups most commonly known as good leaving groups include the halogens~ particularly chlorine, bromine and iodine, para-toluenesulfonyl (tosyl), phenylsulfonyl, methane-sul~onyl ~mesyl), para-bromophenylsulfonyl (brosyl), and azido. It will be noted that when reer~nce is made herein to an alkylating agent having the formula Rl-Z, it is intended that tha alkyl porkion of such alkylating agent can be derivatized, for instance by unsatuxated substituents, aryl substituents, and cycloalkyl ~ubstituents. The term "alkylating agent having the formula Rl-Z" thus includes compounds such as methyl chloride, ethyl bromide, 5-methylheptyltosylate, allyl bromide, 4-hexenyl iodide, 3-ethyl-4-p~ntenyl brosylate, cyclopropyImethyl chloride, cyclobutyl-methyl iodide, cyclohexylmethyl mesylate, 3-tetra-hydxofurylmethyl bromide, 2-furylmsthyl azide, 2-phenylethyl chlo:_de, 3-benzoylpropyl bromide, 2-(3-; ~
, . - ~ . . : ~ . -, . . ~
:. ' ,, ; ' , ' - .' ' '~ ' ' .
: , . . - . . . ~ -. . . :

X~4466K

chlorophenylthio)e-thyl azide, phenoxymethyl bromide, 3-isopropylphenylthiomethyl bromide~ and related groups~
Thus, a 4a-aryl-2,3,4,4a,5,6,7,7a-octa-hydro-lH-2-pyrindine can be reacted with an alkylating agent to provide the corresponding 4a-aryl-2-substituted-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine. Such alkylation reaction is quite general and can be accomplished by reacting the appropriate 4a-aryl-octahydro-lH-2-pyrindine with the appropriate alkylating agent, preferably in an unreactive organic solvent. The alkylating agent typically is utilized in excess amounts, for instance from about 0.5 to abou~ 2.0 molar excess relative to the pyrindine derivative. Unreactive organic solvents commonly utilized in the reaction include ethers such as diethyl ether, dioxane, tetrahydrofuran, as well as solvents such as benzene, dichloromethane, dimethyl-foxmamide, dimethyl sulfoxide, nitromethane, and hexamethylphosphortria~aide. A base is preferably incorporated in the alkylation reaction to act as an acid scavenger since the reaction o~ the pyrindine derivative and the alkylating agent generally is accompanied hy the formation of an acid such as 25 hydrochloric acid or para-toluenesul~onic acid which may act to tie up any unreacted 2-pyrindine derivative as a salt. Bases commonly utili~ed as acid scavengers in such reaction inclu~e sodium bicarbonate, potassium carbonate, sodium hydroxide, triethylamine, and pyridine. Typ.ically, about one equivalent amount of : :

base is employed; however, excessive amounts can be incorporated if desired. The alkylation reaction normally is carried out at an elevated temperature ranging from about 50C. to 200C., and at such temperature, the reaction normally is substantially complete within about 1 to 10 hours; however, long~r reaction times are no-t detrimental and can be used if desired. The product typically is recovered by simply adding wa~ex to the reaction mixture and then extracting the product therefrom in~o a water-immiscible organic solvent such as benzene, ethyl aceta~e, dichloromethane, diethyl ether, chloroform, or related solvents. Upon removal of the solvent from such extracts, for instance by evaporation under reduced pressure, there is obtained the product 4a aryl-2-subs~ituted-2,3,4,4a~5,6,7,7a-octahydro-lH-2-pyrindine, which compound exists either as an oil or as a solid at room temperature. The product so formed can be further purified i desired by standard procedures including chromatography, crystal-lization, distillation, or alternatively such pyrindine product can be converted to an acid addition salt by reaction with an inorganic or organic acid. Such salts routinely are highly crysta}line solids and are readily recrystallized to provide a solid salt of high purity. If de.sired such salt can then be treated with a base such as sodium hydroxide or potassium carbonate, ther~by cleaving the salt to provide the purlied 4a-aryl-2-substituted-2,3,4,4a, $,6,7,7a-octahydro~ 2-pyrindine as a free base.

. .

- , .
- . .. ' '' ' As herebefore indicated, the 2-unsubstituted pyrindine derivatives, namely the 4a-aryl-octahydxo-lH-2~pyrindines, can be converted to a 2-substituted pyrindine derivative which is either a pharmaco-logically useful agent per se, or one which can bereadily converted to a pharmacologically useful agent. For example, reaction of a 4a-aryl-2,3,4,4a,

5,6j7,7a-octahydro-lH-2-pyrindine with an alkylating agent such as 2-benzoylethyl iodide provides the corresponding 4a-aryl-2-(2-b~nzoylethyl)-2,3,4,4a, 5,6,7,7a-octahydro-lH-2~pyrindine, an active analgesic.
If desired, such compound can be reduced at the benzoyl carbonyl moiety, ~or instance by reaction with a reducing agent such as lithium aluminum hydride, to a~fo~d the corresponding 4a-aryl-2-(3-hydroxy-3-phenyl)propyl-2,3,4,4a,5,6,7,7a octahydro-lM 2-pyrindi.ne, also a use~ul analgesic agent. Additionally, a 2-unsubstituted pyrindine derivative can be acylated with any of a number of acylating agents to provide an N-acylated pyrindine derivative, a compound o formula ~I) wherein Rl is O O o R
C-Cl-C7 alkyl, C-R3, and C (CH2)n l-(X)m ~
~5 Such N acylated pyrindines, upon reduction o~ the carbonyl moiety, provide 2-substituted pyrindine derivatives o ~ormula (I) whlch are active analgesics.
Examples of commonly used acylating agents include acetyl chloride, pentanoylchloride, 4-hexenoyl chloride, cyclobutylormyl bromide, 2-(~e~rahydro-. -. ,- - ~ :
~ ~ .
.

~5~2~

furyl)formyl chloride, benzoyl bromide, phenoxyacetyl iodide, 3,4-dimethylphenylacetyl chloride, 3-~2-fluorophenyl)propionyl chloride, phenylthioacetyl bromide, 4-phenyl~3-butenoyl chloride, acetic anhydride, and hexanoic anhydride. The acylation of the 2-unsubsti~uted pyrindine derivative with an acylating agent such as the aforementioned is caxried out by reacting approxim~te~y equimolar quantities of the pyrindine derivative and the acylating agent in an unreactive or~anic selvent such as dichloromethane, ekhanol~ or tetxahydrofuran. The reaction ~ypically utilizes a base ~uch as sodium bicarbonate, potassium carbonate, or propylene oxide to serve as ~n acid scavenger~ The reaction is best carried out at a ~empexature of about -20C. to about 30C., and generally is complete within 1 to 8 hvurs. The product, for example a 4a-aryl-2-acylated-2,3,4,4a, ~,6,7,7a-octahy~ro-lH 2-pyxindine, is readily isolated by simply removing the reaction solvent by evapora~ion.
The product so formed normally is not purified further, but rather is reduced immediately to provide a 4a~-aryl-2-~ubs~ituted~2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine o~ formula (I). Such reduction of the N-acyl carbonyl group can be accomplished by reaction of the acylat~d pyrindine deri.vative wi~h a -: reducing agent ~uch as lithium aluminum hydride or by : catalytic hydrogenation or upon reduction of the hl'7aobond with platin~m oxide and hydrogen.
It will additionally be recognized that ~ l other modifications can be made on certain of , . ,~:~a . .
,..... ..... . ,., ~.

. 9 ' : . . , : . .: - . .
.i : , -,, : , .
- ~ , , . . . . . :
:. . . .. ~ .: . . . .
. , ~ , , .~ :
. . .

.b ~

the 4a-aryl-2-substituted-2,3,4,4a,5,6,7,7a-octa-hydro~ 2-pyrindines of formula (I). For example, while a 4a-aryl pyrindine derivative wherein the aryl group is a 3-hydroxyphenyl moiety can be prepared by starting with a 2-(3-hydroxyphenyl~-2-ethoxycarbonyl-methyl-cyclohexanone and modifying such compound according to the various processes discussed herein-above, it might be preferable to prepare a 4a-(3-methoxyphenyl)-2-substituted-2,3,4,4a,5,5,7,7a~
octahydro-lH-~-pyrindine, and then convert the 3 methoxy group of such 4a-aryl substituent to a hydroxy group. Such conversion is readily accom-plished by reacting a 4a-(3-methoxyphenyl)-pyrindine derivative with hydrobromic acid in acetic acid.
Such reaction is quite general for the conversion of a methoxyphenyl group to a hydroxyphenyl group. The hydroxy group o~ such 4a-(3-hydroxyphenyl)pyrindines can, if desired, be acylated with common Cl-C3 alkanoyl acylating agents, for instance acetyl chloride or propionyl anhydride, thereby providing the corxesponding 4a-(3-alk~noyloxyphenyl~pyrindine derivatives.
As hereinbefore pointed out, ~he 4a-aryl-2-substituted-octahydro-lH ~pyrindine derivatives o~
; 25 formula (I) can be reacted with an organic or in-organic acid so as to provide a crystalline salt which can be purified by crystalli~ation, and which then can be converted back to the pyrindine free base by treatment with a suitable base such as svdium hydroxide. Certain of the acid addition salts are 5~

encompassed within the scope of formula (I).
Specifically, there are included herein the non-toxic pharmaceutically acceptable acid addition salts of the pyrindine bases which are described herein-above. Such non-toxic pharmaceutically acceptable acid addition salts are prepared by reacting a 4a-aryl-2-substituted-octahydro-1~ 2-pyrindine of formula (I) with an organic or an inorganic acid.
Acids commonly used to prepare the pharmaceutically acceptable acid addition salts o~ formula ~I) include the hydrogen halide acids such as hydrogen chloride, hydrogen bromide, and hydrogen iodide, as well as acids such as sulfuric, phosphoric, nitric, perchloric, phosphorous~ nitrous, and related acids. Organic acids commonly used to prepare pharmaceutically acceptable acid addition salts of the pyrindines o ormula (I) include acetic, propionic, ~ toluene-sulfonic, chloroacetic, maleic, tartaric, succinic, oxalic, citric, lactic, palmitic, stearic, benzoic, and related acids. The pharmaceutically acceptable acid addition salts of formula (I) can be conveniently prepared by simply dissolving a 4a-aryl-2-substituted-octahydro lH-2-pyrindine in a suitable solvent such as diethyl ether, ethyl acetate, acetone, or ethanol, and adding to such solution either an equivalent amount or an excess of a suitable acid. The salt so formed normally crystallizes out of solution and can be recovered by fil~ra~ion, and is accordin~ly ready for use as a pharmacological agent, or can be further puriied by recrystallization ~rom cornmon solven~s such as acetone and methanol.
. .

.

.. . . . . ..

2~;

The following list of trans-4a-aryl 2-substituted-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindines is representative of the compounds falling wi~hin the scope of formula (I).
4a-phenyl-2-(3-ethylpentyl)-2,3,4,4a,5,

6,7,7a-octahydro-lH-2-pyrindine;
4a~3-methoxyphenyl)-2-(n-octyl)-2,3,4,4a, 5,6,7,7a-octahydro-lH-2-pyrindinium bromide;
4a-(3~hydroxyphenyl) 2-(2-propenyl)-2,3,4, 4a,5,6,7,7a-octahydro-lH-2-pyrindine;
4a-(3-propoxyphenyl)-2-(2,3-dime~hyl-4-hexenyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine;
4a-phenyl-2-(S-heptenyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium acetate;
4a-~3-hydroxyphenyl)-2-cyclopentylmethyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium oxalate;
4a-(3-ethoxyphenyl)-2-(2-tetrahydrofuryl-methyl)-2,3,4j4a,5,6,7,7a-octahydro-lH-2-pyrindine;
4a-phenyl-2-(2-phenoxye~hyl)-2,3,4,4a,5, ~20 6,7,7a-octahydro-lH-2-pyrindine;
4a-(3-hydroxyphenyl)-2-(2-me.thylphenoxy-methyl)-2,3,4,4a,5,6,7,7a-octahydro-lH~2-pyrindinium succinate;
4a-(3-methoxyphenyl)-2-(3,5-dichlorobenzoyl-25 me~hyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine;
4a-(3-ethoxyphenyl)-2-[3-(3-methyl-4-bromophenyl~-3-hydroxy]propyl-2,3,4,4a~5,6,7,7a-octahydro-lH~2~pyrindinium iodide;
4a-phenyl-2-[3-(2-athyl-6-methylphenylthio)-30 propyl]-2,3,4,4a,5,6,7,7a-octahydro-1~-2-pyrindinium perchlorate;
4a-(3-hydroxyphenyl)~2-[2-(3,4-dibromo-phenyl3~2-hydroxylethyl-2,3;4,4a,5,6t7,7a-~ctahydro-lH-2-pyrindineJ

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X-4466~ -18-4a-phenyl-2-(3-phenylthio)propyl-2,3,4, 4a,5,6,7,7a-octahydro~ 2-pyrindinium citrate, 4a-phenyl-2-[3-(2-isopropylphenyl~propyl-2,3,4,4a,5,6,7,7a-octahydro-lH 2-pyrindinium maleate;
4a-~3-ethoxyphenyl)-2-(2-phenyl-2-hydroxy-ethyl)-2,3,4j4a,5,6,7,7a-ockahydro-1~-2-pyrindinium : phosphate;
4a-phenyl-2-~2-(4-chlorophenyl~-2-hydroxy-ethyl]-2,3,4,4a,5,6,7~7a-octahydro-lH-2-pyrindinium methanesulfonate;
4a-(3-hydroxyphenyl)-2-[3-(2-chloro-3-bromophenyl)-3-hydroxypropyl]-2,3,4,4a,5,6,7,7a-octahydro lH-2-pyrindine;
4a-(3-propoxyphenyl)-2-(2-ethylben20yl-ethyl)-2,3,4l4a,5,6,7,7a-octahydro-lH-2~pyrindinium chloride;
4a-(3-ethoxyphenyl)-2-~3-(2-chlorophenyl-thio)propyl]-2,3,4,4a,5,6~7,7a-octahydro-lH-2-pyrindine;
20 4a-phenyl-2-[3-(2-ethyl-5-bromophenyl)-p~opylJ-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine;
and : 4a-(3-hydroxyphenyl)-2-[2-(3,5-diethyl-phenoxy)ethyl]-2,3,4,4a,5,6,7,7a-octahydro-~H-2-pyrindinium stearate.
It will be not~d ~hat ~he compounds of formula (T) have two asymmetric centers, namely the 4a position and the 7a position. This invention comprehends both separated isomers and racemic mixtures of such lsomers which are useful pharma-cologically as analgesic agonist or antogonist drugs.

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However, only the trans-isomers of formula (I~ are intended thereby, namely, such that the 4a-aryl group is orie~ted on the opposite side of the plane of the molecule from the 7a-Aydrogen atom. Thls lnvention accordingly compxehends the pharmacologically active individual optically-active trans-isomers, in adclition to the racemic mixture o~ trans-isomersO
Such racemic pair of ~rans-octahydropyrindines can be separated into its component stereoisomers by procedures well known in the art. In the event that all useful pharmacologic activity resides in one sterioisomer, the dl-racemate is still useful in that it contains, as a constituent part, the pharma-cologically active isomex.
The process for preparing the 4a,7a-trans isomers, formula (II), comprises catalytic hydrô-genation of a 4a-aryl-hexahydropyrindine, ~ormula (III), specifically a pyrindine having a double bond at the 1,7a-position~ Such hydrogenation generally is carried out by reacting a 4a-aryl-2-alkyl-3,4,4a, 5,6j7-hexahydro-2-pyrindine with hydrogen in th~q presence of a cataly6t such as platinum oxide. The hydrogenation typically is carried out in a solvent such as methanol or ethanol, and routinely is complete within about one to ei.ght hours when carried out at about 25C. under a hydrogen pressuxe of about 2.74 x 106 to about 5.48 x 106 dynes/cm2. The hydro-genation typically provides a mixture of the 1,7a-trans isomer and the 1,7a-cis isomer; however, the trans isomer generally predominates. Separation of .

X-4466K _~o-the isomers can be readily effected by salt forma~ion and crystallization. For example the racemic mixture of octahydropyrindines can be converted to a suitable sal~ ~uch as the picrate or maleatP sal~, and the Cl5 racemate normally crystallizes first from solvents such as diethyl e~her and diisopropyl ether, and can - accordingly be separated from the trans ~y fil~ration.
The trans racemate then can be recovered from the filtrate and purified by reorystallization.
The preparation of the 4a-aryl-octahydro-pyrindines provided by formula (I~ requir~s starting materials, many of which are hitherto unknown and not readily available. For example, the abov2-described preferred method for preparing trans-4a-aryl-2-substituted-octahydro-lH-2~pyrindines requires the corresponding 4a-aryl-2-subs~ituted 3,4,4a,5,6,7-hexahydro-2 pyrindines, i . e, ~1~ 7a-hexahydropyrindines Such compounds can be prepared by condensing phenyl lithium or a 3-substituted phenyl lithium with a 1-alkyl-4-piperidone to provide the corresponding l-alkyl-4-phenyl or substituted phenyl~4-hydro~ypiper-~- idine. Dehydration of the 4-hydroxypiperidine derivative affords a l-alkyl~4-aryl-1,2,3~6-tetra-hydropyridine. The tetrahydropyridine derivative next is reac~ed with a propylene dihalide such as 3-chloropropylbromide to afford a l-alkyl-4-aryl-4~
(3 halopropyl)-1,2,3,4 tetrahydropyridine, which is then readily cyclized by reaction with sodium iodide in acetonitrile to provide the corresponding 4a-aryl-2-alkyl-3,4~4a,5,6,7-hexahydroo2-pyrindine.

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Certain o~ the 4a-axyl-2-substituted octahydro-lH-2-pyrindines of formula (I) have found utility in the treatment of pain, and accordingly can be used to e~fect analgesia in a subject sufering from pain and in need of treatment. Additionally, the pyrindine deriva~ives of foxmula (I) have been found to possess both analgesic agonist and analgesic - antagonist properties, and as such are capable of producing analgesia in a mammal while at the same time, because of the analgesic antagonist activity, having a greatly decreased incidence of addiction liability. Such ability of the compounds disclosed herein to cause analyesic agonist as well as analgesic antagonis~ ef~ects in mammals is thus responsible ~or a decrease in any addictive properties of a parti-cular drug caused by its opiate-like analgesic action. The compounds are thus particularly valuable since they produce analgesia with only minimal physical dependance liability. Certain of the ~ompounds are additionally useul in combating the undesirable effects produced by opiates such as morphine.
The analgesic activity possessed by the compoullds of formula (I) has bee,n determined by testing such compounds in standard animal assays routinely used to measure analgesic action attri-butable to test compounds. Such assays include the mouse-writhing test and the ra~ tail jerk assay.

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The mouse-writhin~ assay is carried out as follows:
Cox standard strain albino male mice, weighing 20-22 grams and fasted overnight, are used. Writhing, wh~ch is characterized by contraction of the abdominal musculature, extension of the hindlegs and rotation of the trunk is induced by the intraperitoneal administration of 55 mg/kg of acetic acid (0O55 percent~. Each treatment group consists of 5 mice.
The total number of writhes for the treatment group is d0ter-mined in a 10-minute observation period starting 5 minutes after acetic acid administrationa Control groups have totals of 200-350 writhes per observation period~ Control and experimental groups are compared and a percent inhibition calculated as follows: f ( Experimental total) Test compounds are administered at lO0 mg/kg by the oral route at 30, 90, and 180 minutes and by the subcutaneous route at 30 minutes be~ore the intraperi~oneal administration of acetic acid.
A second standard assay ~or analgesic activity is the rat tail jerk assay which is carried out as follows:
Female Sprague-Dawley rats weighin~ 70-80 grams that ha~e been fasted overnight are used. Following treatment with either the administration vehicle or the test compound, the animal is placed in a "Plexiglass"* holder. A "Nichrome"**
resistance wire is located between two V-shaped copper tubes ' that serve as a tail restO The tail of the rat is ; placed in the tail rest and the nichrome wire is *Trademark for an acrylic (polymethyl methacrylate) res:in in sheet form~ It i5 highly transparent.
~ *Trademark for a series of nickel alloys containing 54-80% nickel, 10-20% chromium, 7-27% iron, 0-11o copper, 0-5% manganese, 0.3%-4.6% silicon; they have a high specific resistance and are used for heating resistance elements.

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- ~ - -heated by passing electric (AC1 current through it.
Radiant heat from the wire becomes aversive to a normal rat within 6-7 seconds and the rat attempts to " jerk" away from the heat. The elapsed time from the onset of the current in the wire to ~ody " jerk"
of the rat is recorded as the tail jexk reaction time. The average. tail jerk reaction time of a drug~treated group is compared to the average reaction time o a vehicle-treated (control) gxoup using Student's "t" test for statistical signiicance.
These are usually 5 animals per treatment group.
The mean reaction time + S~E. of a typical control group is 6.85 ~ 0.3 seconds.
In the mouse writhing assay, the following 15 E.D.50~s (dose ~my~kg) which decreases the number of writhing observations by 50 percent 30 minutes after administration compared to controls) were obtained or the compounds of formula (I~ and are shown in Table I. Also, in. the rat tail jerk assay, the following E.D.'s (effective dose (mg/kg1 which causes a 2 second increase in reaction time determined after 30 minute~) were obtained for the compounds ; of formula (I) and are al~o shown in Table I.

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* a The 4a-aryl-2-substituted-2,3,4,4a,5,6,

7,7a-octahydro~lH-2-pyrindines o~ formula tI) are thus useful in producin~ analgesia in mammals such as humans. Such compounds can be adminis~ered to a mammal by either the oral or the parenteral route.
It generally is preerred to utilize a pharmaceu-tically acceptable acid addition salt of the pyrindine derivative when the dosage is by the oral route, since such salts are easily formulated for convenient oral administra~ion. For example, one or more pharma-cologically active compounds of formula (I) either as the free base or as a pharmaceutically acceptable acid addition salt~ will be formulated for oral administration by admixing such compounds with any of a number o commonly used diluent~, excipients, or carriers. Examples of such diluents and excipients coammonly employed in pharmaceutical prepaxations include starch powder, sucrose, cellulose, magnesium stearate, lactose, calcium sulfate, sodium benzoate and relat d diluents. Such compositions can be molded in~o tablets or enclosed in telescoping gelatin capsules or conveni nt administration. If desired, the active compounds of formula (I) can additionally be combined wi~h one or more other agents known ~o effeat analgesia, such as caffeine, acetaminophen, and propoxyphene.
The active compounds of formula (I) can addltionally be formulated as sterile aqueous or non aqueous solutions, suspensions, and emulsions for convenien~ parenkeral administration. Non-aqueous . ~ . . .

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vehicles commonly utilized in such formulations include propylene glycol, vegetable oils such as olive oil, as well as various organic esters such as e~hyl oleate. Useful aqueous solutions for oral and parenteral administration include isotonic saline solution.
The precise dosage of ac~ive ingredient, that is the amount of one or more of the pharma-cologically active 4a-aryl-2-sub~tituted-octahydro-lH-2-pyrindines of formula (I) administered to a mammal, such as a human subject for example, may be varied over a relatively wide range, it being neces-sary that the formulations should constitute a proportion of one or more of the active ingredients of formula (I) such that a suitable dosage will be obtained. Such suitable dosage will depend on the particular therapeutic effect desir~d, on the parti-cular route o~ administration being utilized, and on the duration of treatment, as well as ~he precise condition belng treated. Typically the dosages of the active compounds of formula (I) will range from about 1.0 to about 25 mg./kg. o animal body weight per day r appropriately divided for administration from 1 to 4 times per day. Prefexred oral dosages will generally range from about 2 to about 50 mg./kg.
In order to demonstrate more ully the scope of the compounds of formula (I) and their starting ; materials, the following examples are provided by way of illustration.

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X 4466K -27~

STARTING MATERIALS
ExamE~e A
A solution o 159 ml. of n-butyllithium in 100 ml. of hexane oontaining 47.7 g. of 3-methoxy-bromobenzene was s~ixred at -25~C. for twenty minutes a~d then was warmed to room temperature a~d stirred for one hour to provide 3 methoxyphenyl lithium. The xeac~ion mixture was chilled to 10C~ and stirred while a solution of 50 g. of 1-methyl-4-piperidon~ in 100 ml. of diethyl ether was added dropwise over thirty minutes. Following complete addition, the reac~ion mixture was stirred for ~wo hours, and then was diluted with 50 ml. of saturated aqueous sodium chloride solution. The solution was extracted several times wi~h diethyl ether, and the ethereal extracts were combined and concentxated to dxyness to provide 38 g. of 1-methyl-4-hydroxy-4-(3-methoxy-phenyl)piperidine.
~ xam~le B
To a stirred ~olution of 200 ml. o~ 50 g~
o phospho~us pentoxide in me~hanesul~onic acid was added por~ionwise over our minutes 59 g. o 1~
methyl-4~hydroxy 4 (3-hydroxyphenyl)piperidlneO The reac~ion wa~ exothel~mic and the ~emperature rose to 2S 70C. After complete addi~ion of the piperidine derivativa~ th~ r~ac~ion mixture ~as added to 200 g~
o~ ice, and the aqueous mixtuxe was made alkaline by the addi~ion o ammonium hydroxide. The alkaline mixture was extracted several times with diethyl ether, and the ethereal extracts were combined, ~ ' ,.. .: . , . ~

s washed with water, dried, and the solvent was xemoved by evaporation under reduced pressure to provide 44.7 gn of the product as an oil. The oil thus formed was distilled to provide l-methyl-4-~3-methoxyphenyl)~l,2,3,6-tetrahydropyridine, B.P.
123-138~C. a~ 0.1 torr.
Analysis Calc. for C13Hl~NO
Theory: C, 76.81; H, 8.43; N, 6.89.
Found: C, 76052i H, 8.15; N~ 6.67.
~
To a stirred cold (-S to -10C.) solution of 25 g. of 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine in 450 ml. of tetrahydrofuran was added dropwise over thirty minutes 90 ml. of 1.6 molar n-butyl lithium in hexane. Following complete addition, the svlution was stirred ~o~ ten minutes at -10C.
and then cooled to -30C. The cold solution next was added dropwise over twenty minutes to A stirred solution of 73.3 g. of 3-chloropropylbromide in 20 300 ml. of diethyl ether chilled to -50C. Following complete addition, the reaction mixture was warmed to -20C. and diluted with 5~0 ml. of saturated aqueous sodium chloride that had been chilled to 0C.
The organic layer was separated, washed with water, and the product was extracted there~rom into 1200 ml.
o~ lN hydrochloric acid. The aqueous acid layer was washed with diethyl ether and then was made alkaline ! by the dropwise addition of concentrated aqueous I sodi~ hydroxide. The alkaline solution was extracted several times with diethyl ether, and the ethereal ..

.
. ' extracts were combined, washed with water and dried.
Evaporation of ~he solvent at lOQC. afforded an oil which was dissolved in 2500 ml. of acetonitxile containing 52~5 g~ of sodium iodide. The reaction S mixture was heated at reflux and stirred for twenty-four hours, after which time the solvent was removed by evapora~ion under reduced prsssure. The crude product thus formed was dissolved in a mixture of 800 ml. of lN sodium hydroxide an~ 1000 ml. of diethyl ether, and the mixture was stirred vigorously or forty-five minutes. The ethereal layer then was separated, washed with saturated aqueous sodium chloride and dried. Removal of the solvent by evaporation under reduced pressure afforded the product as an oil, which upon distillation provided 21.5 g. o 4a-phenyl-2-methyl-3,4,4a,5,6,7-hexahydro-2~pyrindine. B.P. 110-112C. at 0.075 torr.
Analysis Calc~ for C15HlgN
Theory: C, 84.46; H, 8.98; N, 6.57.
Found: C, 84.74; H, 8.72; N, 6.28 Example D
Following thè procedure set out in Example C, l-methyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine was reac~ed wi~h 3-chloropropylbromide and sodium iodide to a~ord 4a-(3-me~hoxyphenyl)-2-methyl-3,4,4a,5,6,7-hexahydro-2-pyrindine. B.P. 132-134C.
at 0.1 torr.
AnalysiS Cala. for C16H22N
I'heory: C, 78.97; H, 8.70; N, 5.76.
Found: C, 76.58; H, 8.28; N, 5.36.
m/e: theory 243; found 243.

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:: .. . ...
. , . .. , . . . : . . .

FINAL PRODUCTS

A solution o 5.0 g. of 4a-phenyl 1 methyl-3,4,4a,5,6,7-hexahydro-2-pyrindin~ in 5~ ml.
of ethanol containing 500 mg of platinum oxide was stirred at room ~emperature for four hours under a hydrogenatmosphere of 4.13 x 10~ dynes/cm2. The mixture then was fil~ered and ~he solven~ was ramoved from the filtrate by evaporation ~o provide an oil which was shown by NMR and high pressure liquid chroma~ography ~o c~nsist of abou~ forty perc~n~
cis-4a-phenyl-1 methyl-2,3,4,4a;5,6,707a-octahydro-lH 2~pyrindine and about sixty percent of the cor-responding rans isomer~ The mixture was dissolved in 50 mlO of diethyl eth~r and made acidic by the addition of a saturated solution o~ hydrogen bromide dissolved in diethyl ether. Concentration of the - eth real solution efected crystallization~ The mixture was filtered and the precipitate was recrys-: 20 tallized from 30 ml. of i opropanol and 70 ml. of diisopro~yl ether to afford ~.6 g. of _is-4a-phenyl-~; 2 me~hyl~2,3,4,4a~5,6,7~7a-oc~ahydro-lH-2-pyrindinium ~ bromide.
:~- . The ~iltra~e was evapoxatad to dryness and i 25 the residue was di~sol~ed ~n waterO The aqueous ~olution was made alkaline by the addition o lN
: sodium hydroxide, and the aqueous alka}ine solution ~ was extracted wi~h diethyl ether. The ethereal `~ extracts were combined, washed with wa~er a~d dried.
~ 30 Removal o~ the solvent by evaporation under xeduced .
. .
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. .
.
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pressure afforded 2.57 g. of txans-4a-phenyl-2-methyl-2,3,4,4a,5,6,7,7a~octahydro-lH-2~pyrindine.
The trans-pyrindine d~rivative was dis-solved in 120 ml. of ethanol and reacted with 2.76 g.
of picric acid ts provide 2.7 g. of trans-4a-phenyl-2~methyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium picrate. M~P. 167-168C.
Analysis Calc. for C21~24N4O7 Theory: C, 56.75; H, 5.44; N, 12.61.
Found Cr 56~99; EI, 5.65; N, 12.46.
Example 2 The preparation described in Example 1 was repeated except that the trans-pyrindine derivative was reacted with maleic acid and isolated as trans-15 4a-phenyl-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium maleate. M.P. 113-114C.
Analysis Calc. for ClgH25NO4 Theory: C, 68.85; H, 7.60; N, 4.23.
Found: C, 6d.66; H, 7.82; N~ 3.98 Exam~le 3 Following ~he procedure set forth in Example 1, 4a-(3-methoxyphenyl)-2-methyl-3,4,4a,5,6,7-hexa-hydro-2-pyxindine was hydrogenated over platinum oxide to provide a 60:40 mixture of trans~4a-(3-25 methoxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine and the corresponding cis-isomer. rrhe txans-isomex was crystal~ized as the picrate salt~
The trans isomer was isolated as the free base, namely tr _ -4a-~3-methoxyphenyl)-2-methyl~2,3,4,4a, 30 5/6,7,7a-oatahydro-lH-2-pyrindine. M.P. 40-43C.

, . .. - . , : : , . ~ , :: , . ..
.: , . .. . . . ................ - .. , . :. ...
- . : , , - ~ . .

~nalysis Calc. for C16H23N0 Theory: C, 78.32; H, 9.45; N, 5.71.
Found: C, 78026; H, 9.31; N, 5.61.
xam~le 4 . A solution of 3~5 g. of trans-4a-~3-methoxy-phenyl)~2-methyl-2,3,4~4a,5,6,7,7a-octahydro-lH~
2~pyrlndine in 35 ml. of glacial acetic acid con-taining 35 ml. of fifty percent aqueous hydrobromic acid was stirred and heated at reflux for fifteen hours. The reaction mixture then was cooled ~o room temperature and diluted with 100 ml. of ice-water.
The aqueous acid solution was made basic by the addition of concentra~ed sodium hydroxide to pH
9.8, and the aqueous alkaline solution was extracted several times with diethyl ether. The ethereal extracts were combined, washed with water and dried.
Removal of the solvent by evaporation under reduced pressure afforded 1.8 g. of the product as a solîd.
The solid so formed was recrystallized from ~50 ml.
of ethyl acetate to provide 1.65 g. of trans-4a-(3-hydroxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine. M.P. 192-194C.
Analysis Calc. ~or C15H21N0 Theory: C, 77.88; H, 9.15; N, 6.05.
Found: C, 7-7.48; H, 8.7~; N, 5.67.

i 30 . .
. .

, : .,:

- . ~ .

Claims (20)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a trans-compound of the general formula (II) wherein:
R1 is hydrogen, C1-C8 alkyl, CH2R3, or ;

in which:
R3 is C2-C7 alkenyl, C3-C6 cycloalkyl, furyl, or tetrahydrofuryl;
R4 and R5 independently are hydrogen, C1-C3 alkyl, or halogen;
n is 0, 1, 2, or 3;
m is 0 or 1, except that when m is 0, n is other than 0;
X is CO, CHOH, CH=CH, S, or 0, except that when n is 0, X is other than S or 0;
R2 is hydxogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkanoyloxy; and the pharmaceutically acceptable acid addition salts thereof;

which comprises reacting a compound of the general formula (III) wherein:
R1 is hydrogen, C1-C8 alkyl, CH2R?, , alkyl, , or in which:
R? is C3-C6 cycloalkyl, furyl, or tetra-hydrofuryl;
R4 and R5 independently are hydrogen, C1-C3 alkyl, or halogen;
n is 0, 1, 2, or 3;
m is 0 or 1, except that when m is 0, n is other than 0;
X is CO, CHOH, CH=CH, S, or 0, except that when n is 0, X is other than S or 0;

R2 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkanoyloxy;
with hydrogen and platinum oxide, followed by alkylation when R1 is hydrogen to obtain a compound of formula (II) in which R? is defined as before, optionally de-etherifying when R2 is C1-C3 alkoxy to obtain a compound of formula (II) in which R2 is hydroxy, and optionally acylating a compound of formula (II) in which R2 is hydroxy to obtain a compound of formula (II) in which R2 is C1-C3 alkanoyloxy, and, when desired, forming the pharma-ceutically acceptable acid addition salt thereof by conventional means.

2. A trans- compound of the general formula (II) wherein:
R? is hydrogen, C1-C8 alkyl, CH2R3, or ;

in which:
R3 is C2-C7 alkenyl, C3-C6 cycloalkyl, furyl, or tetrahydrofuryl;
R4 and R5 independently are hydrogen, C1-C3 alkyl, or halogen;
n is 0, 1, 2, or 3;
m is 0 or 1, except that when m is 0, n is other than 0, X is CO, CHOH, CH=CH, S, or 0, except that when n is 0, X is other than S or 0;
R2 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkanoyloxy; and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by the process of claim 1 or an obvious chemical equivalent thereof.

3. The process of claim 1 wherein R? is C1-C8 alkyl or CH2R3 in which R3 is C2-C7 alkenyl or C3-C6 cycloalkyl.

4. The compound of claim 2 wherein R? is C1-C8 alkyl or CH2R3 in which R3 is C2-C7 alkenyl or C3-C6 cycloalkyl, whenever prepared by the process of claim 3 or an obvious chemical equivalent thereof.

5. The process of claim 3 wherein R2 is hydroxy or C1-C3 alkoxy.

6. The compound of claim 4 wherein R2 is hydroxy or C1-C3 alkoxy, whenever prepared by the process of claim 5 or an obvious chemical equivalent thereof.

7. The process of claim 5 wherein R2 is methoxy.

8. The compound of claim 6 wherein R2 is methoxy, whenever prepared by the process of claim 7 or an obvious chemical equivalent thereof.

9. The process of claim 5 wherein R2 is hydroxy.

10. The compound of claim 6 wherein R2 is hydroxy, whenever prepared by the process of claim 9 or an obvious chemical equivalent thereof.

11. The process of claim 1 wherein R1 is hydrogen.

12.The compound of claim 2 wherein R1 is C1-C8 alkyl, whenever prepared by the process of claim 11 or an obvious chemical equivalent thereof.

13.The process of claim 1 wherein R1 is C1-C8 alkyl.

14.The compound of claim 2 wherein R1 is C1-C8 alkyl, whenever prepared by the process of claim 13 or an obvious chemical equivalent thereof.

15. The process of claim 1 for preparing trans-4a-phenyl-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-pyrindine which comprises reacting 4a-phenyl-1-methyl-3,4,4a,5,6,7-hexahydro-2-pyrindine with hydrogen and platinum oxide.

16. Trans-4a phenyl-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-pyrindine, whenever prepared by the process of claim 15 or an obvious ohemical equivalent thereof.

17. The process of claim 1 for preparing trans-4a-(3-methoxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a octahydro-1H-2-pyrindine which comprises reacting 4a-(3-methoxyphenyl)-2-methyl-3,4,4a,5,6,7-hexahydro-2-pyrindine with hydrogen and platinum oxide.

18. Trans-4a-(3-methoxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine, whenever prepared by the process of claim 17 or an obvious chemical equivalent thereof.

19. The process of claim 1 for preparing trans-4a-(3-hydroxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine which comprises reacting 4a-(3-methoxyphenyl)-2-methyl-3,4,4a,5,6,7-hexahydro-2-pyrindine with hydrogen and platinum oxide, followed by de-etherifying with glacial acetic acid and aqueous hydrobromic acid.

20. Trans-4a-(3-hydroxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine, whenever prepared by the process of claim 19 or an obvious chemical equivalent thereof.